Lung cancer is the leading cause of cancer death for American women and men, and approximately 90% of these deaths are caused by active cigarette smoking. Environmental tobacco smoke (ETS) exposure is considered a significant lung cancer risk factor for never-smokers. We investigated the hypothesis that never-smoking women, who are exposed to ETS and develop lung cancer, are a genetically susceptible population. Archived tumor tissues were analyzed from 106 never-smoking women enrolled in a case-control study of ETS and lung cancer risk. We analyzed germline polymorphisms in cancer susceptibility genes that activate, i.e., cytochrome p450 1A1 (CYP1A1), and detoxify, i.e., glutathione S-transferase M1 (GSTM1) and GSTT1 chemical carcinogens, found in tobacco smoke. In an analysis limited to patients, the risks associated with the potential susceptibility alleles were compared with that for cumulative ETS exposure, as was determined by a structured interview. Never-smokers without ETS exposure who developed lung cancer (n=55), were compared with the never-smokers with exposure to ETS who developed lung cancer (n=51), and were found more likely to be deficient in glutathione S-transferase M1 (i.e., GSTM1 null) activity due to a genetic polymorphism in the GSTM1 gene (odds ratio = 2.6, 95% confidence interval = 1.1-6.1). A statistically significant rising trend in risk occurred with increasing ETS exposure (two-sided P = 0.02) reaching more than a six-fold excess risk in those exposed to 55 pack-years of ETS. A common genetic polymorphism divides the population of never-smokers into two groups of approximately equal size, one (homozygous carriers of the GSTM1 null allele) that has a statistically significant greater risk of lung cancer from ETS than the other (heterozygous or homozygous carriers of the wild-type GSTM1 allele). The analysis of the p53 mutation spectrum in the lung cancers from this case series is in progress. In addition, we have initiated a large lung cancer case-control study to examine gender differences in cancer risk and the value of the mutagen sensitivity assay in predicting cancer risk. - p, Tumor Suppressor, Radon, Tobacco Smoke, - Human Subjects